Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, New York, NY, USA; Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA.
Sumitomo Dainippon Pharma, Tokyo, Japan.
Lancet Psychiatry. 2021 May;8(5):387-404. doi: 10.1016/S2215-0366(21)00039-0. Epub 2021 Apr 13.
Evidence of comparative benefits of long-acting injectable antipsychotics (LAIs) versus oral antipsychotics for schizophrenia has been inconsistent across study designs. The aim of this study was to evaluate the comparative benefits of LAIs versus oral antipsychotics in three study designs to inform clinical decision making.
We did a comprehensive systematic review and meta-analysis comparing LAIs versus oral antipsychotics for schizophrenia covering three study designs: randomised controlled trials (RCTs), cohort studies, and pre-post studies. Our literature search was without language restrictions, in MEDLINE and PubMed, the Cochrane Library, Scopus, and Embase, for studies published from database inception up to a last search on March 13, 2020. We also searched for unpublished studies and ClinicalTrials.gov. We included studies lasting at least 6 months that targeted adults with schizophrenia and related disorders (>80% of participants). Studies on penfluridol (neither an LAI or daily oral antipsychotic), case reports, and case series with fewer than 20 patients were excluded. Two investigators independently extracted study-level data and resolved disagreement by consensus, or via a third investigator. Study authors were contacted to obtain additional information as needed. For our primary outcome we meta-analysed the risk ratio (RR) for hospitalisation or relapse with LAIs versus oral antipsychotics by a random-effects model, with hospitalisation used preferentially over relapse. As secondary analyses, we reversed the preferential order to relapse over hospitalisation, and assessed hospitalisation risk and relapse risk individually. Other secondary outcomes included all meta-analysable data, classed by relevance to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, and analysed by study design. Dichotomous outcomes were expressed as pooled RR and continuous outcomes as standardised mean difference (SMD). The protocol is registered with PROSPERO (CRD42019142094).
We identified 14 687 records, of which 137 studies (397 319 patients) met the inclusion criteria (32 RCTs [23·4%; 8577 patients], 65 cohort studies [47·4%; 377 447 patients], and 40 pre-post studies [29·2%; 11 295 patients]) and were analysed. The quality of studies in terms of risk of bias varied across study designs and within each study design from low to high. LAIs were associated with a lower risk of hospitalisation or relapse than oral antipsychotics in each of the three study designs (RCTs: 29 studies, 7833 patients, RR 0·88 [95% CI 0·79-0·99], p=0·033; cohort studies: 44 studies, 106 136 patients, RR 0·92 [0·88-0·98], p=0·0044; pre-post studies: 28 studies, 17 876 patients, RR 0·44 [0·39-0·51], p<0·0001). This association was maintained across the study designs when we reversed the preferential order to risk of relapse over hospitalisation, and in individual analysis of hospitalisation risk. The association was maintained only in pre-post studies for relapse risk alone. In all other outcomes related to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, LAIs were more beneficial than oral antipsychotics in 60 (18·3%) of 328 comparisons, not different in 252 (76·8%) comparisons, and less beneficial in 16 (4·9%) comparisons when analysed by study design. Significant heterogeneity was observed across all three study designs. Publication biases were apparent in cohort and pre-post studies, but effect sizes were similar after trim-and-fill analyses.
Although study designs have strengths and weaknesses, including potential low quality of observational studies, we consistently identified significant benefit with LAIs versus oral antipsychotics in preventing hospitalisation or relapse, in settings ranging from restricted research (RCTs) to real-word application (cohort and pre-post studies). Our findings suggest that increased clinical use of LAIs could improve outcomes in schizophrenia.
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For the Chinese, French, German, Italian, Japanese, Portugese and Spanish translations of the abstract see Supplementary Materials section.
长效注射抗精神病药（LAIs）与口服抗精神病药治疗精神分裂症的比较获益证据在不同的研究设计中并不一致。本研究旨在评估三种研究设计中 LAIs 与口服抗精神病药的比较获益，以指导临床决策。
我们进行了一项全面的系统评价和荟萃分析，比较了 LAIs 与口服抗精神病药治疗精神分裂症的情况，涵盖了三种研究设计：随机对照试验（RCT）、队列研究和前后研究。我们的文献检索没有语言限制，检索了 MEDLINE 和 PubMed、Cochrane 图书馆、Scopus 和 Embase，检索时间从数据库建立到 2020 年 3 月 13 日的最后一次搜索。我们还搜索了未发表的研究和 ClinicalTrials.gov。我们纳入了持续时间至少 6 个月的研究，这些研究针对的是成年人的精神分裂症和相关障碍（>80%的参与者）。不包括苯氟奋乃静（既不是 LAI 也不是每日口服抗精神病药）、病例报告和少于 20 例患者的病例系列研究。两名调查员独立提取研究水平的数据，并通过共识或第三名调查员解决分歧。如有需要，我们联系了研究作者以获取其他信息。对于我们的主要结局，我们通过随机效应模型对 LAI 与口服抗精神病药治疗的住院或复发风险进行了荟萃分析，首选住院而不是复发。作为次要分析，我们将优先顺序从复发改为住院，单独评估住院风险和复发风险。其他次要结局包括所有可进行meta 分析的数据，按有效性、疗效、安全性、生活质量、认知功能和其他结局的相关性进行分类，并按研究设计进行分析。二分类结局表示为汇总 RR，连续结局表示为标准化均数差（SMD）。该方案已在 PROSPERO（CRD42019142094）中注册。
我们确定了 14687 条记录，其中 137 项研究（397319 名患者）符合纳入标准（32 项 RCT [23.4%；8577 名患者]、65 项队列研究 [47.4%；377447 名患者]和 40 项前后研究 [29.2%；11295 名患者]）并进行了分析。研究的质量在研究设计中存在差异，在每个研究设计中从低到高均存在差异。在每种研究设计中，LAIs 与口服抗精神病药相比，住院或复发的风险均较低（RCT：29 项研究，7833 名患者，RR 0.88 [95%CI 0.79-0.99]，p=0.033；队列研究：44 项研究，106136 名患者，RR 0.92 [0.88-0.98]，p=0.0044；前后研究：28 项研究，17876 名患者，RR 0.44 [0.39-0.51]，p<0.0001）。当我们将优先顺序从复发改为住院时，这种关联在研究设计中得以维持，在单独分析住院风险时也是如此。仅在前后研究中，复发风险的关联仍然存在。在所有其他与有效性、疗效、安全性、生活质量、认知功能和其他结局相关的结果中，LAIs 在 328 次比较中有 60 次（18.3%）比口服抗精神病药更有益，252 次（76.8%）无差异，16 次（4.9%）较差，按研究设计分析。在所有三种研究设计中都观察到了显著的异质性。在队列研究和前后研究中都出现了发表偏倚，但修剪和填充分析后效果大小相似。
尽管研究设计具有优势和劣势，包括观察性研究质量可能较低，但我们始终发现 LAIs 与口服抗精神病药相比在预防住院或复发方面具有显著优势，这些研究的范围从限制研究（RCT）到实际应用（队列和前后研究）。我们的研究结果表明，增加 LAIs 的临床应用可能会改善精神分裂症的结局。
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对于英文原文中出现的人名、地名等专有名词，以及药物商品名，我均保留其英文原文，未做翻译。
